The discovery that microphages, one kind of immunocompetent cells, produce a large quantity of nitrates led to the discovery that nitrogen monoxide (NO) is biologically synthesized (Proc. Natl. Acad. Sci., U.S.A., Vol. 82, pp. 7738-7742 (1985) and J. Immunol., Vol. 138, pp. 550-565 (1987)). In the field of circulatory organs, a substance having a relaxing action that is released from endothelial cells was discovered and named an endothelial cell-derived relaxing factor (EDRF). It was found later that the substance of EDRF is NO (Nature, Vol. 327, pp. 524-526 (1987)).
NO, which has recently been revealed to be produced biologically, is synthesized through the following route by the action of a nitrogen monoxide synthase (hereinafter abbreviated as NOS) on an L-arginine substrate. ##STR3##
NOS includes at least a constitutive isozyme (endothelial type and neuronal type) and an inducible isozyme. Endothelial NOS exists chiefly in endothelial cells, and its activity is controlled by an intercellular calcium concentration. Neuronal NOS exists in central nervous cells, peripheral nervous cells, islet .beta. cells, gastrointestinal nerves, the medulla of the suprarenal glands, renal macula densa, etc., and its activity is under control by an intercellular calcium concentration similarly to the endothelial type NOS.
The constitutive NOS (inclusive of endothelial type and neuronal type, hereinafter abbreviated as c-NOS) always exist in the cells in amounts almost unchangeable under physiological conditions. On the other hand, the inducible NOS (hereinafter abbreviated as i-NOS) can exist in hepatocytes, neutrophil leucocytes, macrophages, smooth muscle, fibroblasts, mesangium cells, gastrointestinal eliphelium, islet .beta. cells, vascular smooth muscle cells, gliocytes, etc. Usually, the inducible NOS is not observed in cells but induced on stimulation by endotoxins and/or various cytokines.
NO synthesized by the action of NOS exhibits a wide variety of actions, for example, vascular relaxation, inhibition on blood platelet aggregation and adherence, inhibition on leucocyte adherence and migration, inhibition on sympathetic activity, endotoxin shocks, endotoxin- or cytokine-induced hypotension, action as a neurotransmitter, ischemic cerebral cell disturbances, antitumor action, bactericidal action, induction of autoimmune diseases, insulin dependent diabetes mellitus or arthritis, induction of post-transplantation tissue disturbances and graft rejection, and the like.
An NO synthase inhibitor (NOS inhibitor) is not only useful in analyzing the in vivo physiological activities of NO but is expected as a therapeutic agent for shocks or ischemic diseases. Therefore, various NOS inhibitors have recently been developed.
For example, arginine analogues, such as N.omega.-monomethyl-L-arginine (L-NMMA), N.omega.-nitro-L-arginine (L-NNA), N.omega.-amino-L-arginine (L-NAA), and N.omega.-iminoethylornithine (L-NIO), are known as a substrate competitive agent. Known cofactor competitive inhibitors include diphenylene iodonium (DPI), di-2-thienyl iodonium (DTI), and calcineurin. Known gene transcription induction inhibitors include corticosteroid, TGF.beta., IL-4 and IL-10.
WO 96/35677 discloses that a compound represented by formula (A) shown below, a salt thereof, and a pharmaceutically acceptable ester thereof are a nitrogen monoxide synthase inhibitor: ##STR4##
wherein
R.sup.1A is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, alkyloxy, thioalkoxy, cycloalkyl, heterocyclyl, and aryl, which may optionally be substituted by lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, CONR.sup.10A R.sup.11A, S(O)R.sup.10A, S(O).sub.2 R.sup.10A, SO.sub.2 NR.sup.10A R.sup.11A, PO(OR.sup.10A) (OR.sup.11A) amidino, guanidino; wherein all said substitutions may be optionally substituted with one or more of the following: halogen, lower alkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, hydroxy, lower alkoxy, S(O)R.sup.10A, S(O).sub.2 R.sup.10A, amidino, guanidino; PA1 X.sup.A =NR.sup.2A, O, S, SO, SO.sub.2, (CH.sub.2).sub.pA, CH.dbd.CH; PA1 pA=0 to 6; PA1 A.sup.A =NR.sup.3A, O, S, SO, SO.sub.2, (CH.sub.2).sub.qA, CH.dbd.CH; PA1 q.sup.A =0 to 6; PA1 B.sup.A =NR.sup.4A, O, S, SO, SO.sub.2, (CH.sub.2).sub.vA or CH.dbd.CH; PA1 v.sup.A =0 to 6; PA1 R.sup.2A =hydrogen, lower alkyl, aryl, heterocyclyl; PA1 R.sup.3A =hydrogen, lower alkyl, aryl, heterocyclyl; PA1 R.sup.4A =hydrogen, lower alkyl, aryl, heterocyclyl; PA1 R.sup.5A, R.sup.6A and R.sup.7A are independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, heterocyclyl, hydroxy, lower alkoxy, thiol, lower thioalkoxy, S(O)R.sup.9A, S(O).sub.2 R.sup.9A, halogen, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxyl, carboalkoxy, carboaryloxy, carboarylalkyloxy, cyano, aminocarbonylalkoxy, aminocarbonylamino, aminocarbonylaminoalkyl, haloalkyl, SO.sub.2 NR.sup.10A R.sup.11A, wherein all said substitutions may be optionally substituted with one or more of the following: lower alkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoacyl, carboxyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, hydroxy, lower alkoxy; PA1 R.sup.5A and R.sup.6A may be optionally taken together to form an alicyclic, heterocarbon, heterocyclic or aromatic hydrocarbon and said optionally formed ring may be optionally substituted with one or more of the following: lower alkyl, lower alkenyl, lower alkynyl which may be optionally substituted with carboxyl, carboalkoxy, carboaryloxy, carboxyalkylaryloxy and lower alkoxy; PA1 R.sup.8A =hydrogen, hydroxy, O-alkyl; PA1 R.sup.9A =hydrogen, hydroxy, O-alkyl; PA1 R.sup.10A =hydrogen, lower alkyl, alkylaryl, aryl; PA1 R.sup.11A =hydrogen, lower alkyl, alkylaryl, aryl; PA1 R.sup.10A and R.sup.11A, taken together, may be alkylene, resulting in a N-containing heterocycle. PA1 --R.sup.1 -- represents a 3- or 4-membered carbocyclic ring together with the carbon atom or atoms to which it is bonded, said carbocyclic ring being condensed to side d or e of the piperidine ring or bonded to the 4-position of the piperidine ring through a spiro-union; PA1 R.sup.2 represents a C.sub.1-6 alkyl group; PA1 R.sup.3 represents a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group or a halogen atom; PA1 R.sup.4 represents a hydrogen atom, an amino-C.sub.1-4 alkyl group or a carbocyclic ring-C.sub.1-4 alkyl group which may be substituted with an amino-C.sub.1-4 alkyl group; PA1 i represents an integer of 0 to 3; PA1 n represents an integer of 0 to 3; and PA1 the plural R.sup.2 's or R.sup.3 's are the same or different, PA1 or an acid addition salt thereof or a hydrate thereof; PA1 wherein R.sup.5 represents a C.sub.1-6 alkyl group; and other symbols are as defined above, PA1 wherein R.sup.41 represents an amino-C.sub.1-4 alkyl group or a carbocyclic ring-C.sub.1-4 alkyl group which may be substituted with an amino-C.sub.1-4 alkyl group, PA1 R.sup.21 : hydrogen or C.sub.1-6 alkyl group; PA1 R.sup.22 : hydrogen or C.sub.1-6 alkyl group; PA1 R.sup.23 : hydrogen or C.sub.1-6 alkyl group; PA1 R.sup.31 : C.sub.1-6 alkyl group; PA1 R.sup.32 : C.sub.1-6 alkyl group; PA1 X.sup.1 : halogen; PA1 X.sup.2 : halogen; PA1 X.sup.10 : halogen; PA1 Bu.sub.3 SnH: tributyltin hydride; PA1 Ph.sub.3 SnH: triphenyltin hydride; PA1 AIBN: 2,2'-azobisisobutyronitrile; PA1 BF.sub.3.OEt.sub.2 : boron trifluoride diethyl ether complex; PA1 PhSMe: thioanisole; PA1 TFA: trifluoroacetic acid; PA1 Bu.sub.2 CuLi: dibutylcopper lithium; PA1 HMPA: hexamethylphosphoramide; PA1 mCPBA: m-chloroperbenzoic acid; PA1 aliquat-336: tricaprylylmethylammonium chloride; PA1 PMB: p-methoxybenzyl. ##STR9## ##STR10## ##STR11## ##STR12## ##STR13## ##STR14## ##STR15##
WO 95/11231 and WO 96/14844 also teaches that similar compounds serve as a nitrogen monoxide synthase inhibitor.